GA-68-DOTATOC- edotreotide gallium ga-68 injection, solution

Ga-68-DOTATOC by

Drug Labeling and Warnings

Ga-68-DOTATOC by is a Prescription medication manufactured, distributed, or labeled by UIHC – P E T Imaging Center. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    Ga 68 DOTATOC Injection is indicated for use with positron emission tomography (PET) for the localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adult and pediatric patients.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Radiation Safety – Drug Handling

    Handle Ga 68 DOTATOC Injection with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions (5.1)]. Use waterproof gloves, effective radiation shielding and appropriate safety measures when preparing and handling Ga 68 DOTATOC Injection.

    Radiopharmaceuticals should be used by or under the control of physicians who are qualified by specific training and experience in the safe use and handling of radionuclides, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides.

    2.2 Recommended Dosage and Administration Instructions

    Recommended Dosage

    In adults, the recommended amount of radioactivity to be administered for PET imaging is 4 mCi (148 MBq) with a range of 3 mCi to 5 mCi (111 MBq to 185 MBq) administered as an intravenous injection with an injection rate of approximately 10 seconds per mL.

    In pediatric patients, the recommended amount of radioactivity to be administered for PET imaging is 0.043 mCi/kg of body weight (1.59 MBq/kg) with a range of 0.3 mCi (11.1 MBq) to 3 mCi (111 MBq) as an intravenous injection with an injection rate of approximately 10 seconds per mL.

    Administration

    • Use Ga 68 DOTATOC Injection within 3 hours of calibration time.
    • Use aseptic technique and radiation shielding when withdrawing and administering Ga 68 DOTATOC Injection.
    • Inspect Ga 68 DOTATOC Injection visually for particulate matter and discoloration before administration. Do not use the drug if the solution contains particulate matter or is discolored.
    • Calculate the necessary volume to administer based on measured activity, volume, calibration time, and date.
    • Measure the patient dose immediately prior to administration in a dose calibrator.
    • After injection of Ga 68 DOTATOC Injection, administer an intravenous flush of sodium chloride injection, 0.9% to ensure full delivery of the dose.
    • Dispose of any unused drug in a safe manner in compliance with applicable regulations.

    2.3 Use with Somatostatin Analogs and Patient Hydration

    Somatostatin Analogs

    Somatostatin analogs bind to the same somatostatin receptors as Ga 68 DOTATOC

    • Discontinue short-acting somatostatin analogs 24 hours before imaging with Ga 68 DOTATOC Injection.
    • Image patients with Ga 68 DOTATOC Injection just prior to dosing with long-acting analogs of somatostatin [see Drug Interactions (7)].

    Patient Hydration

    Instruct patients to drink water to ensure adequate hydration prior to administration of Ga 68 DOTATOC Injection and to continue to drink and void frequently during the first hours following administration to reduce radiation exposure [see Warnings and Precautions (5.1)].

    2.4 Image Acquisition

    For Ga 68 DOTATOC PET imaging, a whole-body acquisition from the skull vertex to mid-thigh is recommended. Image acquisition can begin at 60 minutes (range 55 to 90 minutes) after the intravenous administration of the Ga 68 DOTATOC Injection. Adapt Ga 68 DOTATOC Injection uptake time and scan duration according to the equipment used, and the patient and tumor characteristics, to obtain the optimal image quality.

    2.5 Image Interpretation

    Ga 68 DOTATOC binds to somatostatin receptors. Based upon the intensity of the signals, PET images obtained using Ga 68 DOTATOC Injection indicate the presence and density of somatostatin receptors in tissues, .Uptake can also be seen in a variety of non-NET tumors that contain somatostatin receptors or as a normal physiologic variant [see Warnings and Precautions (5.2)]. NET tumors that do not bear somatostatin receptors will not be visualized.

    2.6 Radiation Dosimetry

    Estimated radiation absorbed doses per injected activity for organs and tissues of adult patients following an intravenous bolus of Ga 68 DOTATOC Injection are shown in Table 1. Estimated radiation effective doses per injected activity for adult and pediatric patients following an intravenous bolus administration of Ga 68 DOTATOC Injection are shown in Table 2.

    Table 1: Estimated Radiation Absorbed Dose per Injected Activity in Selected Organs with Ga 68 DOTATOC
    SiteAbsorbed Dose (mGy/MBq)
    Urinary bladder wall0.119 ± 0.058
    Spleen0.108 ± 0.065
    Kidney0.082 ± 0.020
    Adrenal gland0.077 ± 0.028
    Liver0.041 ± 0.014
    Red marrow0.016 ± 0.003
    Gallbladder wall0.015 ± 0.001
    Total body0.014 ± 0.002
    Lungs0.007 ± 0.001
    Effective dose (mSv/MBq)0.021 ± 0.003

    The effective radiation dose resulting from the administration of 148 MBq (4 mCi) to an adult weighing 75 kg, is about 3.11 mSv. For an administered activity of 148 MBq (4 mCi) the typical radiation dose to the critical organs, which are the urinary bladder wall, the spleen and the kidneys/adrenals, are about 18 mSv, 16 mSv and 12 mSv, respectively. Because the spleen has one of the highest physiological uptakes, higher uptake and radiation dose to other organs or pathologic tissues may occur in patients with splenectomy.

    Table 2: Estimated Radiation Effective Dose per Injected Activity after a Ga-68 DOTATOC Injection
    AgeModel Weight (kg)Effective Dose per Injection Activity (mSv/MBq)
    Adult73.70.019
    15 years56.80.026
    10 years33.20.041
    5 years19.80.066
    1 year9.70.13
    Newborn3.60.36
  • 3 DOSAGE FORMS AND STRENGTHS

    Injection: Gallium Ga 68 DOTATOC Injection is a clear, colorless solution in a 30 mL multiple-dose vial containing 18.5 MBq/mL to 148 MBq/mL (0.5 mCi/mL to 4 mCi/mL) of Ga 68 DOTATOC Injection at calibration date and time.

  • 4 CONTRAINDICATIONS

    None

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Radiation Risk

    Ga 68 DOTATOC Injection contributes to a patient's overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk of cancer. Ensure safe handling and preparation procedures to protect patients and health care workers from unintentional radiation exposure. Advise patients to hydrate before and after administration and to void frequently after administration [see Dosage and Administration (2.1, 2.3)].

    5.2 Risk for Image Misinterpretation

    The uptake of Ga 68 DOTATOC Injection reflects the level of somatostatin receptor density in NETs, however, uptake can also be seen in a variety of other tumors that also express somatostatin receptors. Increased uptake might also be seen in other non-cancerous pathologic conditions that express somatostatin receptors including thyroid disease or in subacute inflammation, or might occur as a normal physiologic variant (e.g. uncinate process of the pancreas) [see Dosage and Administration (2.5)].

    A negative scan after the administration of Ga 68 DOTATOC Injection in patients who do not have a history of NET disease does not rule out disease [see Clinical Studies (14)].

  • 6 ADVERSE REACTIONS

    Clinical Trial Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

    The safety of Ga-68 DOTATOC injection was evaluated in 334 patients in clinical trials of patients receiving a single dose of Ga-68 DOTATOC injection for imaging known or suspected NET.

    The following adverse reactions occurred at a rate of < 2%:
    Gastrointestinal Disorders: nausea

    The following adverse reactions occurred at a rate of a < 1%
    Skin and Subcutaneous Tissue Disorders: pruritus
    Vascular Disorders: flushing

  • 7 DRUG INTERACTIONS

    Non-radioactive somatostatin analogs bind to the same somatostatin receptors as Ga 68 DOTATOC Injection. Image patients with Ga 68 DOTATOC Injection just prior to dosing with long-acting analogs of somatostatin. Short-acting analogs of somatostatin can be used up to 24 hours before imaging with Ga 68 DOTATOC Injection [see Dosage and Administration (2.3)].

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    There are no available data on the use of Ga 68 DOTATOC Injection in pregnant women to identify a risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with Ga 68 DOTATOC. However, all radiopharmaceuticals, including Ga 68 DOTATOC Injection have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. If considering Ga 68 DOTATOC Injection administration to a pregnant woman, inform the patient of the potential for adverse pregnancy outcomes based on the radiation dose from Ga 68 DOTATOC Injection and the gestational timing of exposure.

    The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.

    8.2 Lactation

    Risk Summary

    There is no information on the presence of Ga 68 DOTATOC in human milk, the effect on the breastfed infant, or the effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Ga 68 DOTATOC Injection and any potential adverse effects on the breastfed child from Ga 68 DOTATOC Injection or from the underlying maternal condition.

    Clinical Considerations

    To decrease exposure to the breastfed infant, advise a lactating woman to interrupt breastfeeding and pump and discard breast milk for 8 hours after Ga 68 DOTATOC Injection administration.

    8.4 Pediatric Use

    The safety and efficacy of Ga 68 DOTATOC Injection have been established in pediatric patients with neuroendocrine tumors. Efficacy is based on data from 14 patients in Study A and B demonstrating the ability of Ga 68 DOTATOC to image NETs [see Clinical Studies (14)]. The safety profile of Ga 68 DOTATOC Injection is similar in adult and pediatric patients with somatostatin receptor positive tumors. The recommended Ga 68 DOTATOC injected dose in pediatric patients is weight based [see Dosage and Administration (2.2)].

    8.5 Geriatric Use

    Clinical studies of Ga 68 DOTATOC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

  • 10 OVERDOSAGE

    In the event of a radiation overdose, reduce the absorbed dose to the patient by increasing the elimination of the radionuclide from the body by reinforced hydration, frequent bladder voiding, and diuretics, if needed. If possible, perform an estimate of the radioactive dose given to the patient.

  • 11 DESCRIPTION

    11.1 Chemical Characteristics

    Ga 68 DOTATOC Injection is a radioactive diagnostic agent for intravenous administration. It contains 3.6 mcg/mL (DOTA-0-Phe1-Tyr3) octreotide, 18.5 MBq/mL to 148 MBq/mL (0.5 mCi to 4 mCi/mL) of Ga 68 DOTATOC at calibration time, and ethanol (10% v/v) in sodium chloride (9 mg/mL) solution (approximately 14 mL volume). Ga 68 DOTATOC Injection is a sterile, pyrogen free, clear, colorless, buffered solution, with a pH between 4 to 8.

    Ga 68 DOTATOC, also known as Gallium-68 (DOTA0-Phe1-Tyr3) octreotide, is a cyclic 8 amino acid peptide with a covalently bound chelator (DOTA). The peptide has the amino acid sequence: H-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH, and contains one disulfide bond. Ga 68 DOTATOC has a molecular weight of 1489.65 g/mol and its chemical structure is shown in Figure 1.

    Figure 1: Chemical Structure of Ga 68 DOTATOC

    Figure 1

    Gallium-68 labeled 2-[4-[2-[[(2R)-1-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-[[(2R,3R)-1,3-dihydroxybutan-2-yl]carbamoyl]-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]-7,10-bis(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid.

    11.2 Physical Characteristics

    Table 3 and Table 4 display the principal radiation emission data and physical decay of Ga 68.

    Gallium-68 (Ga 68) decays with a half-life of 68 minutes to stable Zn 68:

    • 89% through positron emission with a mean energy of 836 keV followed by emission of two 511 keV annihilation photons (178%),
    • 10% through orbital electron capture (with associated X-ray or Auger emissions), and
    • 3% through 13 gamma transitions from 5 excited levels of the daughter Zn 68 nucleus. The most probable prompt gamma emission is a 1088 keV gamma with a 3.2% per decay probability.
    Table 3: Principal Radiation Emission Data (>1%)
    Radiation/Emission% DisintegrationMean Energy (MeV)
    beta+88%0.8360
    beta+1.1%0.3526
    gamma178%0.5110
    gamma3%1.0770
    X-ray2.8%0.0086
    X-ray1.4%0.0086
    Table 4: Physical Decay Chart for Gallium Ga-68
    MinutesFraction Remaining
    01.000
    150.858
    300.736
    600.541
    900.398
    1200.293
    1800.158
    3600.025

    11.3 External Radiation

    Gamma constant: 1.8 × 10-4 mSv/hr per MBq at 1 meter [0.67 mrem/hr per mCi at 1 meter] Table 5 displays the radiation attenuation by lead shielding of Ga 68.

    Table 5: Radiation Attenuation of 511 keV Photons by Lead (Pb) Shielding
    Shield Thickness
    (Pb) mm    		Coefficient of Attenuation
    60.5
    120.25
    170.1
    340.01
    510.001
  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Ga 68 DOTATOC binds to somatostatin receptors, with highest affinity (Ki = 2.5± 0.5 nanomolar) for subtype 2 receptors (sstr2). Ga 68 DOTATOC binds to cells that express somatostatin receptors including malignant neuroendocrine cells, which overexpress sstr2 receptors. Gallium 68 is a β+ emitting radionuclide with associated 511 keV annihilation photons that allow positron emission tomography (PET) imaging.

    12.2 Pharmacodynamics

    The relationship between Ga 68 DOTATOC plasma concentrations and successful imaging was not explored in clinical trials.

    12.3 Pharmacokinetics

    Distribution

    Ga 68 DOTATOC distributes to all sstr2-expressing organs such as pituitary, thyroid, spleen, adrenals, kidney, pancreas, prostate, liver, and salivary glands. Uptake in the lung and lymph nodes are lower as compared to other sstr-2 expressing organs.

    Elimination

    Radiotracer elimination is exclusively via urine. Approximately 16% of the injected dose is excreted in urine in the first two to four hours post-injection.

  • 14 CLINICAL STUDIES

    The safety and efficacy of Ga-68 DOTATOC Injection were established in two single-center, open-label studies (Study A and Study B) in which 282 patients with known or suspected SSTR-positive NETs received a single dose of Ga-68 DOTATOC. A total of 238 of the 282 patients (84%) had a history of neoplasm at the time of Ga-68 DOTATOC imaging. Among the 282 patients, 59% were female and 95% white; the mean age was 54 years (range from 4 to 82 years).

    The Ga-68 DOTATOC images were rated by two independent readers blinded to clinical information as either positive or negative for NET within each patient. The imaging results were compared to a composite reference consisting of histopathology and imaging (MR, CT, or In-111 pentetreotide imaging) acquired within 1 year of the Ga-68 DOTATOC imaging, as well as chromogranin A and pancreastatin levels. The proportion of patients positive for NET per composite reference who were identified as positive by the Ga-68 DOTATOC image was used to quantify positive percent agreement. The proportion of patients without NET per composite reference who were identified as negative by the Ga-68 DOTATOC image was used to quantify negative percent agreement.

    Study A (NCT: 01619865) included 220 subjects with known or suspected SSTR positive tumors referred for diagnosis or evaluation of disease extension before or after treatment. A total of 178 of the 220 patients (81%) had a history of neoplasm at the time of Ga-68 DOTATOC imaging. In 177 of the 220 patients, sufficient data to establish NET status per composite reference was available for efficacy evaluation. Table 6 shows the performance of Ga-68 DOTATOC in the detection of NETs for Study A.

    Table 6: Study A. Performance of Ga-68 DOTATOC in the detection of NET by reader
    N = 177NET status as identified by readerReference
    PositiveNegative
    N: number of patients, CI: confidence interval,
  • * Percent reader agreement with reference;
  • † Exact method
    		•
    Reader 1Positive1215
    Negative1239
       
    Agreement (%)* (95% CI)†91 (85, 95)89 (75, 96)
    Reader 2Positive1206
    Negative1338
       
    Agreement (%)* (95% CI)†90 (84, 95)86 (73, 95)

    Study B (NCT: 01869725) included 62 patients with histologically positive NET or other SSTR positive tumor referred for evaluation of disease before or after treatment. In 59 of the 62 patients, sufficient data to establish NET status per composite reference was available for efficacy evaluation. The estimated positive and negative percent agreements were 92% and 75% for reader 1 and 90% and 75% for reader 2, respectively.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Ga 68 DOTATOC Injection is supplied in a multiple-dose, capped 30 mL glass vial containing 18.5 MBq/mL to 148 MBq/mL (0.5 mCi/mL to 4 mCi/mL) of Ga 68 DOTATOC at calibration time in approximately 14 mL of solution (NDC: 24417-681-30).

    Store Ga 68 DOTATOC Injection upright in a lead shielded container at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

    Receipt, transfer, handling, possession or use of this product is subject to the radioactive material regulations and licensing requirements of the U.S. Nuclear Regulatory Commission, Agreement States or Licensing States as appropriate. Store and dispose of Ga 68 DOTATOC Injection in accordance with the regulations and a general license, or its equivalent, of an Agreement State or a Licensing State.

  • 17 PATIENT COUNSELING INFORMATION

    Radiation Risk

    Advise patients to drink water to ensure adequate hydration prior to their PET study and recommend they drink and urinate as often as possible during the first hours following the administration of Ga 68 DOTATOC Injection, in order to reduce radiation exposure [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

    Lactation

    Advise a lactating woman to interrupt breastfeeding and pump and discard breast milk for 8 hours after Ga 68 DOTATOC Injection administration in order to minimize radiation exposure to a breastfed infant [see Use in Specific Populations (8.2)].

  • SPL UNCLASSIFIED SECTION

    Manufactured and Distributed by:
    UIHC – P E T Imaging Center
    0911Z JPP
    200 Hawkins Drive
    Iowa City, IA 52242

  • PRINCIPAL DISPLAY PANEL - 14 mL Vial Label

    DOTATOC Ga 68 INJECTION

    BATCH#
    Diagnostic - For intravenous Use Only
    Contains: 18.5 MBq/mL to 148 MBq/mL (0.5 mCi/mL to 4 mCi/mL) of no-carrier
    added Ga-68 DOTATOC @ end of synthesis; 9 mg/mL of sodium chloride

    Rx ONLY

    Sterile, non-pyrogenic

    Multiple-dose Vial

    NDC# 24417-681-30

    Manufactured by:
    UIHC-PET Imaging Center
    200 Hawkins Drive
    Iowa City, IA 52242

    TOTAL ACTIVITY: mCi
    TOTAL VOLUME: mL
    RADIOACTIVE CONCENTRATION: mCi/mL @ EOS TIME
    EOS TIME:
    EXPIRATION TIME:

    Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F–86°F);
    Store upright in a lead shielded container. Expires 3 hours from end of synthesis.
    See full prescribing information for dosage and administration information.

    Do not use if cloudy or if contains particulate matter.
    CAUTION: RADIOACTIVE MATERIAL

    PRINCIPAL DISPLAY PANEL - 14 mL Vial Label
  • INGREDIENTS AND APPEARANCE
    GA-68-DOTATOC 
    edotreotide gallium ga-68 injection, solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 24417-681
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    EDOTREOTIDE GALLIUM GA-68 (UNII: Y68179SY2L) (EDOTREOTIDE GALLIUM GA-68 - UNII:Y68179SY2L) EDOTREOTIDE GALLIUM GA-684 mCi  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    ALCOHOL (UNII: 3K9958V90M)  
    sodium chloride (UNII: 451W47IQ8X)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 24417-681-3014 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product09/01/2019
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA21082809/01/2019
    Labeler - UIHC – P E T Imaging Center (063513265)
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